Extension of the thrombolytic time window with minocycline in experimental stroke.
OBJECTIVE
Thrombolysis with tPA is the only FDA-approved therapy for acute ischemic stroke. But its widespread application remains limited by narrow treatment time windows and the related risks of cerebral hemorrhage. In this study, we ask whether minocycline can prevent tPA-associated cerebral hemorrhage and extend the reperfusion window in an experimental stroke model in rats.


METHODS
Spontaneously hypertensive rats were subjected to embolic focal ischemia using homologous clots and treated with: saline at 1 hour; early tPA at 1 hour, delayed tPA at 6 hours; minocycline at 4 hours; combined minocycline at 4 hours plus tPA at 6 hours. Infarct volumes and hemorrhagic transformation were quantified at 24 hours. Gelatin zymography was used to measure blood levels of circulating matrix metalloproteinase-9 (MMP-9).


RESULTS
Early 1-hour thrombolysis restored perfusion and reduced infarction. Late 6-hour tPA did not decrease infarction but instead worsened hemorrhagic conversion. Combining minocycline with delayed 6-hour tPA decreased plasma MMP-9 levels, reduced infarction, and ameliorated brain hemorrhage. Blood levels of MMP-9 were also significantly correlated with volumes of infarction and hemorrhage.


CONCLUSIONS
Combination therapy with minocycline may extend tPA treatment time windows in ischemic stroke.
Murata
Yoshihiro
Y
Neuroprotection Res Lab, Charlestown, MA 02129, USA.
Rosell
Anna
A
Scannevin
Robert H
RH
Rhodes
Kenneth J
KJ
Wang
Xiaoying
X
Lo
Eng H
EH
D000818:Animals; D015415:Biomarkers; D001812:Blood-Brain Barrier / Q000187:drug effects; D002545:Brain Ischemia / Q000097:blood / Q000188:drug therapy* / Q000201:enzymology / Q000209:etiology; D002543:Cerebral Hemorrhage / Q000097:blood / Q000139:chemically induced / Q000201:enzymology / Q000517:prevention & control; D002544:Cerebral Infarction / Q000097:blood / Q000201:enzymology / Q000209:etiology / Q000517:prevention & control; D004334:Drug Administration Schedule; D004353:Drug Evaluation, Preclinical; D005343:Fibrinolytic Agents / Q000008:administration & dosage / Q000009:adverse effects / Q000627:therapeutic use*; D020766:Intracranial Embolism / Q000097:blood / Q000150:complications / Q000188:drug therapy* / Q000201:enzymology; D008297:Male; D020780:Matrix Metalloproteinase 9 / Q000097:blood; D061965:Matrix Metalloproteinase Inhibitors; D008911:Minocycline / Q000008:administration & dosage / Q000627:therapeutic use*; D018696:Neuroprotective Agents / Q000008:administration & dosage / Q000627:therapeutic use*; D051381:Rats; D011918:Rats, Inbred SHR; D011994:Recombinant Proteins / Q000008:administration & dosage / Q000009:adverse effects / Q000627:therapeutic use; D015424:Reperfusion; D015912:Thrombolytic Therapy / Q000009:adverse effects / Q000379:methods*; D013997:Time Factors; D010959:Tissue Plasminogen Activator / Q000008:administration & dosage / Q000009:adverse effects / Q000627:therapeutic use*
D015415:Biomarkers; D005343:Fibrinolytic Agents; D061965:Matrix Metalloproteinase Inhibitors; D018696:Neuroprotective Agents; D011994:Recombinant Proteins; D010959:Tissue Plasminogen Activator; D020780:Matrix Metalloproteinase 9; D008911:Minocycline